title: PDZ domains and viral infection: versatile potentials of HPV-PDZ interactions in relation to malignancy.
abstract: Cervical cancer is caused by high-risk human papillomaviruses (HPVs), and a unique characteristic of these is a PDZ (PSD-95/Dlg/[ZO-1-)binding motif in their E6 proteins. Through this motif HPV E6 interacts with a variety of PDZ domain-containing proteins and targets them mainly for degradation. These E6-PDZ interactions exhibit extraordinarily different functions in relation to HPV-induced malignancy, depending upon various cellular contexts; for example, Dlg and Scrib show different distribution patterns from what is seen in normal epithelium, both in localization and in amount, and their loss may be a late-stage marker in malignant progression. Recent studies show that interactions with specific forms of the proteins may have oncogenic potential. In addition, it is interesting that PDZ proteins make a contribution to the stabilization of E6 and viral episomal maintenance during the course of HPV life cycle. Various posttranslational modifications also greatly affect their functions. Phosphorylation of hDlg and hScrib by certain kinases regulates several important signaling cascades, and E6-PDZ interactions themselves are regulated through PKA-dependent phosphorylation. Thus these interactions naturally have great potential for both predictive and therapeutic applications, and, with development of screening tools for identifying novel targets of their interactions, comprehensive spatiotemporal analysis is currently underway.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000074288:Discs Large Homolog 1 Protein; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054731:PDZ Domains / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000235:genetics / Q000821:virology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D004268:DNA-Binding Proteins; D000074288:Discs Large Homolog 1 Protein; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins